ADVENTIST MEDICAL CENTER COLLEGE

BACHELOR OF SCIENCE IN PHARMACY

(3rd level)

SUBMITTED BY
ENGUITO, MYKA DOMINEE

BOMBONGAN, ELEANOR A.

SUBMITTED TO:
GERSALE, ARIANE DEAN RPh

SUMMARY II
PHARMACOLOGY 2
 I. OVERVIEW II. PHYSIOLOGY OF MUSCLE CONTRACTION
MYOCARDIUM: (like smooth & skeletal muscle)
HEART FAILURE: is a complex, progressive disorder in  RESPOND TO STIMULATION by:
which the heart is unable to pump sufficient blood to meet the needs
of the body. DEPOLARIZATION RETURN: to resting
DUE to an: impaired ability of the of membrane state (repolarization)
CARDINAL SYMPTOMS:
heart to adequately fill with and/or
dyspnea, fatigue, fluid retention
eject blood.
 Often ACCOMPANIED by: abnormal in BLOOD VOLUME & SHORTENING of ENDS: w/ relaxtion
INTERSTITIAL FLUID. contractile proteins and

 UNDERLYING CAUSES:
a. Arteriosclerotic heart disease CARDIAC MYOCYTES: (cardiac muscle cells)
b. Myocardial infarction Interconnected in groups; RESPONDING AS A UNIT to a stimuli
c. Hypertensive heart disease  CONTRACTING TOGETHER even a single cell is stimulated
d. Valvular heart disease
e. Dilated cardiomyopathy
f. Congenital heart disease

A. ROLE OF PHYSIOLOGIC
COMPENSATORY MECHANISM
(in progression of heart failure)
CHRONIC ACTIVATION: A. ACTION POTENTIAL
 SNS
 RAAS
} ASSOCIATED w/ remodeling of: CARDIAC MYOCYTES:
cardiac tissue, loss of myocytes,
hypertrophy and fibrosis.  ELECTRICALLY excitable
 SPONTANEOUS intrinsic rhythm
PROMPTS additional: neurohormonal o GENERATED BY: specialized “pacemaker” cells
- Location: sinoatrial and atrioventricular (AV) nodes
activation  creation of vicious cycle

if LEFT UNTREATED: leads to DEATH

B. GOALS OF PHARMACOLOGIC
INTERVENTION (in heart failure)
 alleviate symptoms
 slow disease progression GOAL OF TREATMENT
 improve survival

7 classes of drugs 1/> OF DRUG CLASSES may

(shown to be effective) be ADMI depending on
1. ACE (-)  Severity of HF
2. ARB’s  Individual px factors
3. Aldosterone antagonists PHARMACOLOGIC intervention
4. Β-blockers provides ff. benefits:
5. Diuretics  Reduced myocardial work load “Pacemakers”
6. Direct vaso- and  Extracellular fluid of heart
venodilators  Improved cardiac contractility
7. Inotropic agents  Reduced rate of cardiac remodeling Sinoatrial (SA) node or sinus
node is the heart's natural
pacemaker. It's a small mass
KNOWLEDGE of CARDIAC MUSCLE CONTRACTION of specialized cells in the top
PHYSIOLOGY essential for understanding of the right atrium (upper
 COMPENSATORY RESPONSES evoked by failing heart chamber of the heart). It
 ACTION OF DRUGS used to treat heart failure produces the electrical
impulses that cause your
heart to beat.
 CARDIA MYOCYTES (additional) B. CARDIAC CONTRACTION
 have UNUSUAL LONG ACTION POTENTIAL
with 5 phases (Phase 0 to 4)
FORCE OF CONTRACTION: DIRECTLY RELATED to
CONCENTRATION OF FREE (unbound) cytosolic calcium.
NOTES CORNER
What is the difference between So, AGENTS that intracellular Ca2+ levels
pacemaker cells and contractile cells? (or that sensitivity of contractile machinery to Calcium)
= the FORCE of CONTRACTION (inotropic effect)
Pacemaker cells set the rate of the heartbeat. Have no
organized sarcomeres like NOTE
Contractile cells: contribute to the contractile force Inotropic agents: contractility of the <3 by DIRECT
of the heart. or INDIRECT alter in mechanisms that control the
concentration of intracellular calcium.
There are several different pacemakers in the heart
but the sinoatrial node (SA) is the fastest.

C. COMPENSATORY
PHASE 0: Fast upstroke PHYSIOLOGICAL RESPONSE
 NA+ CHANNEL OPEN (fast channels) resulting in fast
in heart failure
inward current
 UPSTROKE ENDS as Na+ channels are rapidly inactivated.
Evokes 3 MAJOR COMPENSATORY
 SODIUM CURRENT is blocked by antiarrhythmic agents
MECHANISMS to ENHANCE CARDIAC
such as quinidine.
OUTPUT
Note: Tho beneficial but ultimately result in FURTHER
PHASE 1: Partial Repolarization DETERIORATION of cardiac function.
 INITIAL RAPID PHASE due to:
a. Inactivation of Na+ channel 1. INCREASED SYMPATHETIC ACTIVITY:
b. K+ channels: that rapidly open and close
- CAUSING: transient outward current. 1. Baroreceptors
Cardiac PRELOAD (stretch on heart) sense in BP
PHASE 2: Plateau = Cardiac OUTPUT
 VOLTAGE-SENSITIVIVE Ca2+ channels open: this
- RESULTING: slow inward (depolarization) current 5. In add: compensatory
 BALACING: slow outward (polarizing) leak of K+ VASOCONSTRICTION responses: 2. Activate the SNS
enhance venous return
& cardiac preload WORK OF HEART
PHASE 3: Repolarization
 CA2+ CHANNELS CLOSE In long term: contributes
 K+ CHANNELS OPEN: FURTHER decline in CARDIAC
- RESULTING: outward current FUNCTION
o LEADS: membrane REPOLARIZATION 4. Result: Increased 3.In attempt sustain
 NET RESULT OF ACTION (to this point): heart rate & greater tissue entry:
a. NET GAIN OF Na+ force of contraction stimulate β-
(of <3 muscle) adreneric receptor
b. LOSS of K+:

THIS IMBALANCE BALANCED by: 2. ACTIVATION OF THE RAAS

Na+ /K+-ATPase. RESULT:
BV increases and
Fall in CARDIAC • increase AFTERLOAD
(peripheral resistance) more BLOOD
OUTPUT
PHASE 4: Forward Current • RETENTION: Na+ and H2O returned to <3
 Depolarization results from:
- Gradual in Sodium permeability
if <3 unable to
 SPOTANEOUS DEPOLARIZATION: automatically brings the cell DECREASE: flow to and RELEASE of pump this volume
to THRESHOLD of the NEXT ACTION POTENTIAL. kidney ALDOSTERONE • Venous pressure increase
• Peripheral & pulmonary
edema occur

Ca+ channel blocker

Verapamil, Diltiazem
Increased formation
Release of renin INCREASE WORK OF
of AG2
HEART
K+ channel blocker
Amiodarone, Sotalol

this
compensatory
responses:
Na+ channel blocker
1a (moderate): Quinidine, Procainamide WORK OF HEART
1b (weak): Lidocaine, Phenytoin Β-blocker
1c: (strong): Flecainide, Propafenone Propanolol, Metoprolol In long term: contributes
FURTHER decline in CARDIAC FUNCTION
3. MYOCARDIAL HYPERTROPHY E. THERAPEUTIC STRATEGIES
in heart failure

I. CHRONIC heart failure

managed by:

a. Fluid limitation (<1.5 – 2 L daily)

b. Low dietary intake of Sodium
(<2000mg/d)
c. Treatment of comorbid conditions
d. Judicious use of
i. diuretics,
ii. (-)ors of the RAAS
INCREASE <3 size; chambers dilate & more globular iii. (-)ors of the SNS
(initially)
 Stretching heart muscle  stronger contraction of heart INOTROPIC agents:
 reserved for ACUTE HF SIGNS and
 Excessive fiber elongation  WEAKER contaction SYMPTOMS (mostly inpatient setting)
 DIMINISH ability
to EJECT BLOOD
} SYSTOLIC failure or HF w/ reduced
ejection fraction (HFrEF): RESULT FROM: II. DRUGS that may
ventricular unable to pump effectively precipitate or exacerbate
heart failure
(less common): PX w/ HF may have “diastolic dysfunction”
 NSAIDS (nonsteroidal anti-
DIASTOLIC DYSFUNCTION: ability of ventricles to RELAX and ACCEPT blood is
inflammatory drugs)
IMPAIRED by STRUCTURAL CHANGES such as Hypertrophy.
 Alcohol
ability of <3 muscle to RELAX due to:  Nondihydropyridine Ca2+
a. Thickening of ventricular wall
channel blockers
b. Subsequence decrease in ventricular volume
 (some) Antiarrhythmic drugs
Does not FILL ADEQUATELY  inadequate CARDIAC OUTPUT Should be avoided if possible.
termed “diastolic HF” or “HF w/ preserved ejection fraction”

DIASTOLIC DYSFUNCTION: (pure form) characterized by SIGNS and SYMPTOMS of HF

In the PRESENCE OF NORMAL FUNCTION OF LEFT VENTRICLE

But BOTH SYSTOLIC and DIASTOLIC DYSFUNCTION (commonly)

coexist in heart failure

D. ACUTE (decompensated) HF

If ADAPTIVE MECHANISMS adequately RESTORE cardiac output

= Heart Failure is compensated.
if FAIL to MAINTAN cardiac output
 Heart failure is decompensated
 Patient develops worsening heart failure signs &
symptoms.

TYPICAL HF signs & symptoms

Dyspnea on exertion ; orthopnea ;

paroxysmal nocturnal dyspnea ; fatigue ; and
peripheral edema,
 III. (-) or RAAS PHARMACOKINETICS
HF leads to: ACTIVATION of RAAS via 2 mechanisms o ORAL
o FOOD: may DECREASE ABSORPTION of captopril (taken:
1) RENIN RELEASE empty stomach)
By: juxtaglomerular cells (in renal afferent arterioles) o PRODRUGS (required: activation) by LIVER (hydrolysis)
Due: diminished renal perfusion pressure o RENAL elimination (all ACTIVE moiety)
Produced by: failing <3 Except: fosinopril
o Half-lives (active compound): 2 to 12 hrs
2) RENIN RELEASE Though: (-) of ACE is much LONGER
By: juxtaglomerular cells promoted by:
a. Sympathetic stimulation
b. β receptors activation ADVERSE EFFECTS
Postural hypotension ; renal insufficiency ; hyperkalemia ;
 AG2 (potent vc) PRODUCTION and its subsequent persistent dry cough ; angioedema (rare)

 STIMULATION OF ALDOSTERONE RELEASE

o POTASSIUM lvl: must be monitored esp concurrent use of
CAUSED salt and water retention a. Supplements

LEADS to both
b. Sparing diuretics
c. Aldosterone antagonists
} due to: HYPERKALEMIA
- PRELOAD
- }
AFTERLOAD characteristic of failing heart
o SERUM creatinine lvl: must be monitored
esp px w/ RENAL DISEASE
o SYMPTOMATIC HYPOTENSION (more common)
Detrimental effects on cardiac muscle, favoring If USED concomitantly w/: DIURETIC
- Remodeling, fibrosis, & inflammatory changes
TERATOGENIC – X pregnant women

A. ACE INHIBITORS B. ARBS

o Part of STD pharmacotherapy in HFrEF  ORAL active compounds
 COMPETITIVE ANTAGONISTS of Ag2 II type 1 receptor
o BLOCK AG2 (potent VC) production
VD { = o Secretion of ALDOSTERONE
 COMPLETE BLOCKAGE of AG2 vs ACE (-) that only (-) 1 enzyme
responsible for AG2 production.
o DIMINISH INACTIVATION of bradykinin (potent VD).  DO NOT AFFECT: bradykinin lvl
 SIMILAR ACTION  ACE (-) but NOT therapeutically identical
 SUBSTITUTE for ACE (-) for px who cannot tolerate the latter.

ACTIONS (on heart)

ACTIONS
o DIFFERENT MOA w/ ace (-) but
o Vascular resistance (afterload) & venous tone (preload) = CO o SAME on PRELOAD & AFTERLOAD
o BLUNT AG2-mediated epinephrine & aldosterone (seen in HF)
o USE: as substitute for ace (-) in px w/ severe cough or
o IMPROVE clinical signs & symptoms (HF)
angioedema
o SHOWN to significantly improve PX SURVIVAL in HF
o USED: tx of hypertension

INDICATIONS PHARMACOKINETICS
1. PX w/ asymptomatic & symptomatic HFrEF  ORAL (active) ; 1x daily dose except Valsartan (2x/day)
2. Px w/ all stages of left ventricular failure  HIGH plasma protein bound except Candesartan (large VOD)
3. PX w/ LOWEST EJECTION fraction (greatest benefit w/ ace)  Losartan: differs, as
4. USED in combo w/ a. prototype of the class
i.
Diuretics b. undergoes extensive 1st-pass hepatic metabolism
ii.
Β-blockers c. incl: conversion to its active metabolites.
iii.
Digoxin Depending on the  OTHER DRUGS: inactive metabolites
iv.
Aldosterone antagonists severity of HF, ACE  URINE & FECES: elimination of metabolites n’ parent compounds
v.
Hydralazine/ isosorbidedinitrate (-) may be
fixed-dose como ADVERSE EFFECTS
5. PX (recent) myocardial infarction SAME ADE n’ DRUG INTERACTION w/ ACE (-)
o PX high at risk for CARDIOvascular event } benefits for BUT, lower incidence of cough and angioedema
o TX hypertension longer term use
CONTRAINDICATED: pregnant
ACE (-) therapy
 C. ALDOSTERONE ANTAGONISTS DIURETICS
DRUG ALL ABOUTS
DIRECT ANTAGONIST of aldosterone,  RELIEVE: pulmonary congestion & peripheral edema
Spironolactone
preventing salt retention ; myocardial  USEFUL: reduced symptoms of volume overload (inc:
hypertrophy ; hypokalemia orthopnea & paroxysmal nocturnal dyspnea
COMPETITIVE ANTAGONIST of  PLASMA VOLUME & venous return to <3 (preload)
aldosterone at mineralocorticoid receptors
 CARDIAC WORKLOAD & OXYGEN DEMAND
- Same action to Spironolactone@MR
Eplerenone - Lower incidence of endocrine-related  also: AFTERLOAD (by: reducing plasma volume) = BP
effects vs Spironolactone
a. Glucocorticoid
Reduced  LOOP DIURETICS: most common use in HF.
Affinity b. Androgen
- USED: px require extensive diuresis & renal insufficiency
c. Progesterone
NOT SHOWN: to improve survival in
OVERDOSE: can lead to
HF, so USED only to treat signs &
profound hypovolemia
symptoms of volume excess.
NOTE:
Patient w/ ADVANCED <3 DISEASE have elevated lvl of
ALDOSTERONE due to AG2 stimulation & reduced
hepatic clearance of the hormone VASO- and VENODILATORS
ALDOSTERONE ANTAGONISTS: indicated for px w/
 DILATED VENOUS = cardiac preload = venous capacitance
- MORE SEVERE STAGES of HFrEF or HFrEF  NITRATES: commonly used venus dilators reduced preload
and recent myocardial infarction for px w/ chronic HF.
 ARTERIAL DILATORS: such as Hydralazine
Hydralazine: reduced systemic arteriolar resistance &
decreased afterload.
RARELY: associated w/ drug-induced lupus
Βeta-blockers
COMBO OF Hydralazine and isosorbide dinitrate
 Patient INTOLERANCE of ACE (-) or Beta-blockers
 Evidence shown improved in systolic function and  or IF ADDITIONAL VASODILATOR RESPONSE is required.
remodeling in pxs receiving
 .
Although, seem COUNTERINTUITIVE CAUTION w/ other drugs: that show FIXED-DOSE: improve symptoms and survival in black pxs w/
 . to ADMI drugs w/ AV conduction such as: HFrEF on STD TREATMENT (Beta-blocker + ACE (-) or ARB)
 .
Negative inotropic activity in HF Amiodarone, verapamil, diltiazem
COMMON ADVERSE EFFECTS:
 BENEFITS arise: despite occasional, initial exacerbation of headache ; hypotension; tachycardia
symptoms.
 BENEFITS attributed to: prevent changes that occur (due:
chronic activation of SNS)
 AGENTS: heart rate & (-) renin release INOTROPIC DRUGS
 In +: PREVENT: deleterious effect of NOREPI on cardiac
muscle fibers. POSITIVE INOTROPIC agents: enhance cardiac contractility
= remodeling, hypertrophy, & cell death.
- cardiac output
3 drugs that shown benefit to HEART FAILURE
Bisoprolol ; carvedilol ; metoprolol succinate RESULT of: cytoplasmic Ca2+ concentration
β -blockade: recommended for all pxs w/ chronic, stable HF - Enhance: cardiac muscle contraction
Treatment: should start @low doses & gradually titrated to target
dose based on px tolerance and vital signs ALL POSITIVE inotropes (HFrEF): Ca2+ concentration
= REDUCED SURVIVAL esp patients w/ HFrEF due to
DRUGS MOA OTHER INFO Coronary heart disease
Bisoprolol - Nonselective β-adrenoceptor
ANTAGONIST
Morbidity & Mortality

- also BLOCKS: α-adrenoceptors

Substrate of P- SO ONLY USED for: SHORT PERIOD
β1 –selective antagonist
Reduced

metabolized: cytochrome P450 2D6 glycoprotein (P-gp) (mainly in patient setting)

Carvedilol
isoenzyme Effects if COADMI w/ Except: DIGOXIN
P-gp (-)
inhibitors: of this
Metoprolol
succinate levels of drugs and risk of AE
 A. DIGITALIS GLYCOSIDES c. NEUROHORMONAL INHIBITION
Digoxin: (-) sympathetic activation w/ minimal effects on
contractility.
( DIGITALIS / DIGITALIS GLYCOSIDES / REASON WHY: lower serum drug conc is targeted in HFrEF.
CARDIAC GLYCOSIDES )

Plant: Digitalis (foxglove)
- groups with similar chemical compounds
- that contractility of heart muscle
- so USED: in treating HEART FAILURE
Digitalis Glycosides:
- LOW THERAPEUTIC INDEX
(therapeutic dose – toxic / even FATAL)
Digoxin: most widely used.
Digitoxin: seldom used due to considerable DOA.
THERAPEUTIC USE
 INDICATED: patients w/ severe HFeRF
AFTER INITIATION of ACE (-) ; beta-blockers & diuretic therapy
 LOW SERUM CONC: is beneficial to HFrEF
(0.5 to 0.8ng/mL)
 SEEN: reduction in HF and improved survival
 HIGHER SERUM CONC: admission is prevented ; mortality increases
Digoxin
CONTRAINDICATED
PATIENT w/ DIASTOLIC FIBRILLATION or right-sided HF
unless PATIENT has concomitant atrial fibrillation or flutter

ACTION
MILD-MODERATE HF: can respond to
a. REGULATION OF CYSTOLIC Ca2+ concentration:
ACE (-), beta-blockers, aldosterone antagonists,
Digoxin: (-) Na+/K+ ATPase enzyme direct vaso- & venodilators and diuretics
= reduced ability of MYOCYTE to actively pump Na+ from Digoxin: many not require
cell.

DECREASE Na+ concentration gradient so
DECREASE ability of Na+ / Ca2+ exchanger
to move Calcium out of cell
So, INCREASED Na+ extracellular and Ca2+
intracellular
so, there is now a SMALL, but
PHYSIOLOGICALLY important increased in
free Ca2+
Ca2+ is no available for contraction
cycle of cardiac muscle = INCREASED
CONTRACTILITY
BUT, when Na+/K+ ATPase enzyme (-) by DIGOXIN:
Resting membrane potential may increased:
- 70mV instead -90mV
MAKES MEMBRANE MORE EXCITABLE
= risk of arrhythmias (toxicity)
b. CONTRACTILITY (of cardiac muscle)
Digoxin:FORCE OF CARDIAC CONTRACTION
= cardiac output that closely resembles of the normal heart.
= vagal tone is also enhanced so both
a. Heart rate
b. Myocardial oxygen demand
: SLOWS CONDUCTON VELOCITY through AV NODE
 Making it USEFUL for atrial fibrillation.
PHARMACOKINETICS
 ORAL and INJECT form | large VOLUME of DISTRIBUTION
since it accumulates in muscle.
 DOSAGE based: lean body weight
 LOADING DOSE REGIMEN used: in acute situations
(such symptomatic atrial fibrillation)
 LONG HALF-LIFE: 30 to 40 hours
 ELIMINATED: intact  kidney
REQUIRE: dose adjustment in renal dysfunction.
ADVERSE EFFECTS
 LOW SERUM CONC: well tolerated USE: toxic lvl
 NARROW THERAPEUTIC INDEX are infrequent
 Digoxin toxicity: common ADR causing hospitalization
INITIAL INDICATORS: anorexia, nausea, vomiting
also EXPERIENCE: blurred vision, yellowish vision
(xanthopsia) & various cardiac arrhythmias.
- TOXICITY MANAGED by:
a. Discontinuance
b. Determine serum K+ lvl and
c. Replenishing potassium (if indicated)
- SEVERE TOXICITY: result to ventricular tachycardia
May require ADMI of
a. Antiarrhythmic drugs
b. Use of antibodies to digoxin (digoxine immune Fab)
Bind & inactivate drugs
DECREASED LEVELS of SERUM POTASSIUM
Predispose px to Digoxin toxicity (since normally
competes w/ K+ for same binding site: Na+/K+ ATPase pump

NOTE: in NORMAL HEART Prone to HYPOKALEMIA:

Positive inotropic effects of DIGITALIS px receiving THIAZIDE or LOOP DIURETICS DIGOXIN:
caution used w/
glycosides is a. Beta-blockers
counteracted by: compensatory b. Verapamil
Clarithromycin, verapamil, Amiodarone: can significantly
autonomic reflexes c. Diltiazem
Digoxin (substrate of P-gp) since they are (-) of P-gp,
That slow AV
needing/necessitating reduced dose of Digoxin
conduction
 BETA-ADRENERGIC AGONISTS ORDER OF THERAPY
DOBUTAMINE & DOPAMINE: improve cardiac performance NOTE: as DISEASE progresses,
By causing: polytherapy is needed
a. positive inotropic effects
b. vasodilation

Both: be given IV DOBUTAMINE: Dietary sodim restriction;

USED: short-term most commonly used diuretics and digoxin
tx of acute HF INOTROPIC AGENTS vs
in hospital setting
DIGOXIN STAGE C All patient: ACE (-), beta-blockers
Structural heart disease, Select: aldosterone antagonist
previous or current symptoms and FDC HYD/ISDN

Beta-adrenergic AGONIST
STAGE B All patients: ACE & ARBS
= cAMP (intracellular cyclic adenosine monophosphate) Structural heart disease, no Select: Beta-blocker
symptoms
 ACTIVATION: PROTEIN KINASE
Some patients: ACE (-) or ARBS
Tx hypertension, diabetes,
dyslipidemia
Increase cAMP
STAGE A
High risk w/ no Risk factor reduction; patient
symptoms education
Activate: protein ENHANCED
kinase CONTRACTION

LOOP DIURETICS: for px w/ overt HF

Phosphorylates
so, INCREASED  FIRST INTRODUCED: for
ENTRY of Ca2+
slow Ca2+
channels
to myocardial - relief of signs & symptoms or
cells
- volume overload (such: dyspnea & peripheral edema)
ACE (-) or ADDED: after optimization
of diuretic therapy
PHOSPHODIESTERASE INHIBITORS ARBS (if ACE not tolerated)
DOSAGE IS GRADUALLY TITRATED to which is
Milrinone: phosphodiesterase (-) - MAXIMALLY TOLERATED and/or
- PRODUCE OPTIMAL CARDIAC OUTPUT
 cAMP
 Same w/ beta-adrenergic agonist BETA-BLOCKERS (historically): added after
RESULTS: calcium (intracellular) optimization ACE (-) or ARB
RESULTS: cardiac contractility
NEWLY DIAGNOSED w/ HFrEF: initiated on LOW DOSES of
 LONG TERM USED: substantial risk of mortality a. Ace inhibitor After initial stabilization
 SHORT-TERM ( IV): not associated w/ mortality in b. Beta-blocker
These agents: slowly TITRATED to optimal levels to
patient WITHOUT HISTORY of INCREASE TOLERABILITY
 Coronary artery disease
 SYMPTOMATIC BENEFIT: may be obtain in patients
w/ refractory HF
o DIGOXIN ;
Initiated on px who
o ALDOSTERONE ANTAGONIST & CONTINUE to HAVE
HF SYMPTOMS
o FIXED-DOSE HYDRALAZINE AND despite optimal
doses of
o ISOSORBIDE DINITRATE: ACE (-) and beta-
blocker
CHAPTER 20: ARRYTHMICS ANTIARRYTHMIC DRUGS

What is Arrythmias? Class I Antiarrhythmic Drugs

 a problem with the rate or rhythm of the MOA:

heartbeat  (-) voltage-sensitive sodium (Na+) channels
 heart’s electrical impulses fire improperly use of sodium channel blockers has declined
causing an abnormal heartbeat due to their proarrhythmic effects

 the heart can beat too fast or too slow

 too fast – tachycardia
 too slow – bradycardia

TYPES OF ARRYTHMIA
ATRIAL SUPRAVENTRICULAR VENTRICULAR
ARRYTHMIAS TACHYCARDIAS TACHYCARDIAS

Ventricular
Atrial AV Nodal Fibrillation
Flutter Reentry (not
responding to
electrical
defibrillation)
Acute USE DEPENDENCE:
Atrial Acute Ventricular  bind more rapidly to open or inactivated Na+
Fibrillation Supraventricular Tachycardia channels
Tachycardia  these drugs show a greater degree of
blockade in tissues that are frequently
Common cause of death in depolarizing
pxs who have had  This property is called use dependence
(or state dependence)
myocardial infarction
 enables these drugs to block cells that are
discharging at an abnormally high
frequency

CAUSES:
Class IA Antiarrhythmic Drugs
 Abnormal automaticity
 Abnormalities in impulse conduction  They have concomitant class III activity
 Current heart attack or scar tissue from  they can precipitate arrhythmias that can
a previous attack progress to ventricular fibrillation
 Specific health issues:
 sleep apnea CLASS IA DRUGS:
 diabetes
 stress  Quinidine
 Procainamide
 high blood pressure
 Disopyramide
 thyroid problems
QUINIDINE
 prototype class IA drug
MOA:
 binds to open and inactivated sodium
channels and prevents sodium influx
slows down the rapid upstroke during
phase 0
 decreases the slope of phase 4
spontaneous depolarization
 (-) K+ channels and blocks Ca+ channels
it slows conduction velocity and
increases refractoriness
 has mild α-adrenergic blocking and
anticholinergic actions
THERAPEUTIC USES:
 available in an intravenous formulation only
 treat acute atrial and ventricular arrhythmias
 Amiodarone replaced Procainamide for clinical
use
PHARMACOKINETICS:
 short duration of action of 2 to 3 hours
 acetylated in the liver to N-acetylprocainamide
(NAPA)
has properties and side effects of a class
III drug
prolongs the duration of the action
potential
eliminated via the kidney

THERAPEUTIC USES: ADVERSE EFFECTS:

 treatment of a wide variety of arrhythmias  Intravenous administration may cause
 including atrial hypotension

 AV junctional
DISOPYRAMIDE
 ventricular tachyarrhythmias
MOA:
PHARMACOKINETICS:  actions like Quinidine
 Quinidine sulfate or gluconate  more anticholinergic activity than
rapidly and almost completely absorbed after oral Procainamide
administration  no α-blocking activity
 rapidly and almost completely absorbed after oral
administration THERAPEUTIC USES:
forming active metabolites
 treatment of ventricular arrhythmias
 alternative to procainamide or quinidine
ADVERSE EFFECTS:  used for maintenance of sinus rhythm in
 may induce the symptoms of cinchonism atrial fibrillation or flutter
 should be used with caution with potent inhibitors
of CYP3A4
PHARMACOKINETICS:
PROCAINAMIDE  well absorbed after oral administration
 metabolized in the liver to a less active metabolite
MOA: and several inactive metabolites

 actions like Quinidine  substrate of CYP3A4

 less anticholinergic activity

 no α-blocking activity ADVERSE EFFECTS:
 should be used with caution with potent
inhibitors of CYP3A4
  has the most anticholinergic adverse effects of the THERAPEUTIC USES:
class IA drugs
 dry mouth Lidocaine
 urinary retention
 Alternative for ventricular fibrillation or pulseless
 blurred vision
ventricular tachycardia (VT)
 constipation
 used in polymorphic VT
 combination with amiodarone for VT storm
CLASS IA DRUGS  has little effect on atrial or AV junction
QUINIDINE  Tx for wide variety arrhythmias
of arrhythmias
PROCAINAMIDE  treat acute atrial and Mexiletine
ventricular arrhythmias
DISOPYRAMIDE  treatment of ventricular
 used for chronic treatment of ventricular
arrhythmias arrhythmias
 maintenance of sinus  often in combination with amiodarone
rhythm

PHARMACOKINETICS:
Class IB Antiarrhythmic Drugs
Lidocaine
 rapidly associate and dissociate from sodium
channels  given intravenously
 the actions of class IB agents are manifested when  drug is dealkylated to two less active metabolites,
the cardiac cell is depolarized or firing rapidly primarily by CYP1A2 with a minor role by CYP3A4

CLASS IB DRUGS:
 a high extraction drug

 Lidocaine
Mexiletine
 Mexiletine

 well absorbed after oral administration

MOA:  metabolized in the liver primarily by CYP2D6 to
inactive metabolites
 In addition to sodium channel blockade,
lidocaine and mexiletine shorten phase 3
repolarization and decrease the duration of the
ADVERSE EFFECTS:
action potential
Lidocaine
 has a fairly wide therapeutic index
 shows little impairment of left ventricular function
 has no negative inotropic effect
 Central nervous system (CNS) effects
 Nystagmus
 Drowsiness
 slurred speech
 limit the duration of continuous infusions
Mexiletine Propafenone

 has a narrow therapeutic index  restricted mostly to atrial arrhythmias

 caution should be used when
administering the drug with inhibitors of PHARMACOKINETICS:
CYP2D6
 Nausea
 Vomiting Flecainide
 Dyspepsia
 absorbed orally and is metabolized by CYP2D6 to
multiple metabolites
 parent drug and metabolites are mostly
Class IC Antiarrhythmic Drugs eliminated renally

 These drugs slowly dissociate from resting sodium

channels and show prominent effects even at Propafenone
normal heart rates
 metabolized to active metabolites primarily via
CLASS IB DRUGS: CYP2D6, and also by CYP1A2 and CYP3A4
 Flecainide  metabolites are excreted in the urine and the
 Propafenone feces

MOA: ADVERSE EFFECTS:

Flecainide
Flecainide
 blurred vision
 suppresses phase 0 upstroke in Purkinje and
myocardial fibers  dizziness
 blocks potassium channels  dizziness

Propafenone
Propafenone
 bronchospasm
 slows conduction in all cardiac tissues (due to its β-blocking effects)
 does not block potassium channels
 inhibitor of P-glycoprotein
Class II Antiarrhythmic Drugs
THERAPEUTIC USES:

Flecainide CLASS II DRUGS:

 maintenance of sinus rhythm in atrial flutter or
fibrillation  Metoprolol
 treating refractory ventricular arrhythmias  Propranolol
 has a negative inotropic effect and can aggravate  Esmolol
chronic heart failure

MOA of CLASS II:

 β-adrenergic antagonists
 β-blockers
 AMIODARONE
THERAPEUTIC USES:
 least proarrhythmic of the class I and III
 useful in treating tachyarrhythmias antiarrhythmic drugs
 used for atrial flutter and fibrillation and for AV
nodal reentrant tachycardia
MOA:
 β-blockers prevent life-threatening ventricular
arrhythmias following a myocardial infarction  shows class I, II, III, and IV actions
 α-blocking activity
CLASS II DRUGS MOA and USES  dominant effect is prolongation of the action
 β-blocker most widely potential duration and the refractory period by
Metoprolol blocking K+ channels
 used in the treatment of
cardiac arrhythmias
THERAPEUTIC USES:
 nonselective β-blockers
Propranolol  treatment of severe refractory supraventricular
 reduces the risk of
and ventricular tachyarrhythmias
bronchospasm
 very-short-acting β-
 mainstay of therapy for the rhythm management
Esmolol of atrial fibrillation or flutter
blocker
 used for intravenous  most commonly employed antiarrhythmic
administration in acute PHARMACOKINETICS:
arrhythmias
 incompletely absorbed after oral administration
 unusual prolonged half-life of several weeks
Class III Antiarrhythmic Drugs ADVERSE EFFECTS:
CLASS II DRUGS:
 pulmonary fibrosis

 Amiodarone  neuropathy

 Dronedarone  hepatotoxicity
 Sotalol  corneal deposits
 Dofetilide  optic neuritis
 Ibutilide  blue-gray skin discoloration
 hypo- or hyperthyroidism

MOA of CLASS II: DRONEDARONE

 block potassium channels
 diminish the outward potassium current during  benzofuran amiodarone derivative
repolarization of cardiac cell less lipophilic
 prolong the duration of the action potential lower tissue accumulation
has a shorter serum half-life than amiodarone

MOA:
 has class I, II, III, and IV actions
THERAPEUTIC USES: ADVERSE EFFECTS:
 used to maintain sinus rhythm in atrial fibrillation  has a low rate of adverse effects when
or flutter
compared to other antiarrhythmic agents
less effective than amiodarone
DOFETILIDE
ADVERSE EFFECTS: MOA:
 pure K+ channel blocker
 has a better adverse effect profile than
amiodarone
THERAPEUTIC USES:
 may still cause liver failure  first-line antiarrhythmic agent in patients with:
 persistent atrial fibrillation
CONTRAINDICATIONS:  heart failure
 coronary artery disease
 with symptomatic heart failure
 permanent atrial fibrillation PHARMACOKINETICS:
 half-life of this oral drug is 10 hours
 drug is mainly excreted unchanged in the urine
SOTALOL

 is most often initiated in the hospital to monitor

CONTRAINDICATIONS:
QT interval
 contraindicated with drugs that
inhibit active tubular secretion
MOA:
 potent nonselective β-blocker activity IBUTILIDE
l-sotalol has β-blocking activity
d-sotalol has class III antiarrhythmic
action MOA:
 blocks a rapid outward potassium current, known  K+ channel blocker
as the delayed rectifier activates the inward sodium current
prolongs both repolarization and duration (mixed class III and IA action)
of the action potential
lengthening the effective refractory THERAPEUTIC USES:
period  DOC for atrial flutter, but electrical cardioversion
has supplanted its use
(replaced)
THERAPEUTIC USES:
- commonly used for these indications in patients with left
PHARMACOKINETICS:
ventricular hypertrophy or atherosclerotic heart disease
- used for maintenance of normal sinus rhythm in patients
 not used orally
Because of the risk of QT prolongation and
with:
Proarrhythmia, Ibutilide initiation is limited to
 atrial fibrillation the inpatient setting.
 atrial flutter  undergoes extensive first-pass metabolism
 refractory paroxysmal supraventricular
tachycardia
 treatment of ventricular arrhythmias
Class III Antiarrhythmic Drugs THERAPEUTIC USES:
CLASS II DRUGS:
 used to control ventricular response rate in atrial
fibrillation and flutter
 Verapamil
 Ditiazem
ADENOSINE
MOA:
Verapamil
THERAPEUTIC USES:
 nondihydropyridine calcium channel blockers  Intravenous adenosine is the DOC for abolishing
 shows greater action on the heart than on acute supraventricular tachycardia
vascular smooth muscle
 bind only to open depolarized voltage-sensitive PHARMACOKINETICS:
channels  extremely short duration of action (approximately
10 to 15 seconds)
Diltiazem

 nondihydropyridine calcium channel blockers ADVERSE EFFECTS:

 bind only to open depolarized voltage-sensitive
channels  has low toxicity
 flushing
THERAPEUTIC USES:  chest pain
 effective against atrial than against ventricular  hypotension
arrhythmias
 tx for reentrant supraventricular tachycardia
MAGNESIUM SULFATE
 reducing the ventricular rate in atrial flutter and
fibrillation
 is necessary for the transport of sodium, calcium,
 Dosage adjustments may be needed in patients and potassium across cell membranes
with hepatic dysfunction

MOA:
Other Antiarrhythmic Drugs
OTHER DRUGS:  slows the rate of SA node impulse formation
prolongs conduction time along the myocardial
tissue
 Digoxin
 Adenosine
THERAPEUTIC USES:
 Magnesium sulfate
 magnesium sulfate - treat arrhythmias
DIGOXIN  magnesium is not effective in the setting of
arrhythmia
MOA:  DOC for treating the potentially fatal arrhythmia
torsades de pointes and digoxin-induced
 (-) the Na+/K+-ATPase pump arrhythmias
 ultimately shortening the refractory period in
atrial and ventricular myocardial cells
prolonging the effective refractory period and
diminishing conduction velocity in the AV node